Mouse model of amyotrophic lateral sclerosis and/or frontotemporal lobar degeneration

Abstract

To generate an animal model exhibiting symptoms similar to those of human amyotrophic lateral sclerosis and/or human frontotemporal lobar degeneration. An animal model exhibiting symptoms similar to those of human amyotrophic lateral sclerosis and/or human frontotemporal lobar degeneration can be produced by means of generating a mutation in a vertebrate so that expression of a mutant protein with a substitution of tyrosine for alanine at a position corresponding to position 382 of SEQ ID NO. 1 or a mutant protein with a substitution of cysteine for glycine at a position corresponding to position 348 of SEQ ID NO. 1 is regulated by an endogenous TDP-43 gene promoter in at least one allele of an endogenous TDP-43 gene of the vertebrate.

1 . A non-human vertebrate wherein expression of a mutant protein with a substitution of tyrosine for alanine at a position corresponding to position 382 of SEQ ID NO. 1 or a mutant protein with a substitution of cysteine for glycine at a position corresponding to position 348 of SEQ ID NO. 1 is regulated by an endogenous TDP-43 gene promoter in at least one allele of an endogenous TDP-43 gene. 
     
     
         2 . The vertebrate according to  claim 1 , wherein the vertebrate has a mutation in which tyrosine is substituted for alanine at a position corresponding to position 382 of SEQ ID NO. 1 or a mutation in which cysteine is substituted for glycine at a position corresponding to position 348 of SEQ ID NO. 1, by an exogenous DNA, in at least one allele of the endogenous TDP-43 gene. 
     
     
         3 . The vertebrate according to  claim 1 , wherein the vertebrate is an animal model of amyotrophic lateral sclerosis. 
     
     
         4 . The vertebrate according to  claim 1 , wherein the vertebrate is an animal model of frontotemporal lobar degeneration. 
     
     
         5 . The vertebrate according to  claim 1 , wherein the vertebrate is a knock-in mouse carrying a human TDP-43 gene. 
     
     
         6 . A method of generating an animal model of amyotrophic lateral sclerosis, comprising the step of generating a mutation in a non-human vertebrate so that expression of a mutant protein with a substitution of tyrosine for alanine at a position corresponding to position 382 of SEQ ID NO. 1 or a mutant protein with a substitution of cysteine for glycine at a position corresponding to position 348 of SEQ ID NO. 1 is regulated by an endogenous TDP-43 gene promoter in at least one allele of an endogenous TDP-43 gene of the vertebrate. 
     
     
         7 . The method according to  claim 6 , wherein a mutation is generated in the vertebrate through the step of substituting tyrosine for alanine at a position corresponding to position 382 of SEQ ID NO. 1 or the step of substituting cysteine for glycine at a position corresponding to position 348 of SEQ ID NO. 1, by an exogenous DNA, in at least one allele of the endogenous TDP-43 gene of the vertebrate. 
     
     
         8 . The method according to  claim 7 , wherein the endogenous TDP-43 gene or a portion thereof, of the vertebrate is replaced with an exogenous human TDP-43 gene or a portion thereof. 
     
     
         9 . The method of producing an animal model of frontotemporal lobar degeneration, comprising the step of generating a mutation in a non-human vertebrate so that expression of a mutant protein with a substitution of tyrosine for alanine at a position corresponding to position 382 of SEQ ID NO. 1 or a mutant protein with a substitution of cysteine for glycine at a position corresponding to position 348 of SEQ ID NO. 1 is regulated by an endogenous TDP-43 gene promoter in at least one allele of the endogenous TDP-43 gene of the vertebrate. 
     
     
         10 . The method according to  claim 9 , wherein a mutation is generated in the vertebrate by means of substituting tyrosine for alanine at a position corresponding to position 382 of SEQ ID NO. 1 or substituting cysteine for glycine at a position corresponding to position 348 of SEQ ID NO. 1, by an exogenous DNA, in at least one allele of the endogenous TDP-43 gene of the vertebrate. 
     
     
         11 . The method according to  claim 10 , wherein the endogenous TDP-43 gene or a portion thereof, of the vertebrate is replaced with an exogenous human TDP-43 gene or a portion thereof.